Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges.

Since the identification of the first disorder of mitochondrial fatty acid oxidation defects (FAOD) in 1973, more than 20 defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders, which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.

Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study.

Alpha-mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha-mannosidase deficiency that leads to the accumulation of mannose-rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product, is the first enzyme replacement therapy indicated to treat non-neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long-term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open-label study evaluated the safety and efficacy of long-term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion-related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.

BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. RESULTS: Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (Pfrom 0 <0.001) and -0.92 mL/min/1.73 m2/year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2/year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. CONCLUSIONS: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.

Individual and Family Determinants for Quality of Life in Parents of Children with Inborn Errors of Metabolism Requiring a Restricted Diet: A Multilevel Analysis Approach.

OBJECTIVE: The objective of this study was to compare the quality of life (QoL) for parents of children with inborn errors of metabolism (IEMs) requiring a restricted diet with French population norms and investigate parental QoL determinants. STUDY DESIGN: This cross-sectional study included mothers and/or fathers of children < 18 years of age affected by IEMs requiring a restricted diet (except phenylketonuria) from January 2015 to December 2017. Parents' QoL was assessed using the World Health Organization Quality of Life BREF questionnaire and compared with age- and sex-matched reference values from the French general population. Linear mixed models were used to examine the effects of demographic, socioeconomic, disease-related, and psychocognitive factors on parental QoL, according to a 2-level regression model considering individuals (parents) nested within families. RESULTS: Of the 1156 parents invited to participate, 785 (68%) were included. Compared with the general population, parents of children with IEMs requiring a restricted diet reported a lower QoL in physical and social relationship domains but a higher QoL in the psychological domain. In the multivariate analysis, characteristics associated with poorer parental QoL included both parent-related factors (being a father, older age, more educated parent, nonworking parent, greater anxiety, seeking more social support, and using less positive thinking and problem-solving coping strategies) and family-related factors (disease complications, increased number of hospital medical providers, child's younger age, single-parent family, and lower family material wealth). CONCLUSION: Parents of children with IEMs requiring a restricted diet reported poorer QoL in physical and social relationship domains than population norms. Psychocognitive factors, beyond disease-specific and family-related characteristics, were the most important determinants influencing parental QoL and may represent essential aspects for interventions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02552784.

Understanding the challenges, unmet needs, and expectations of mucopolysaccharidoses I, II and VI patients and their caregivers in France: a survey study.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by defective enzyme activity involved in the catalysis of glycosaminoglycans. Published data on adult patients with MPS remains scarce. Therefore, the present qualitative survey study was aimed at understanding knowledge of the disease, unmet needs, expectations, care, and overall medical management of adult/adolescent patients with MPS I, II and VI and their caregivers in France. RESULTS: A total of 25 patients (MPS I, np = 11; MPS II, np = 9; MPS VI, np = 5) were included and about 36 in-depth interviews (caregivers alone, nc = 8; patients-caregiver pair, nc+p = 22; patients alone, np = 6) were conducted. Except one (aged 17 years), all patients were adults (median age: 29 years [17-50]) and diagnosed at median age of 4 years [0.4-30], with mainly mothers as caregivers (nc = 16/19). Patients were classified into three groups: Group A, Patients not able to answer the survey question because of a severe cognitive impairment (np = 8); Group B, Patients able to answer the survey question with low or no cognitive impairment and high motor disability (np = 10); and Group C, Patients able to answer the survey question with low or no cognitive impairment and low motor disability (np = 7). All groups were assessed for impact of disease on their daily lives based on a scale of 0-10. Caregivers in Group A were found to be most negatively affected by the disease, except for professional activity, which was most significantly impacted in Group B (4.7 vs. 5.4). The use of orthopaedic/medical equipments, was more prevalent in Groups A and B, versus Group C. Pain management was one of the global unmet need expressed by all groups. Group A caregivers expected better support from childcare facilities, disability clinics, and smooth transition from paediatric care to adult medicine. Similarly, Group B caregivers expected better specialised schools, whereas Group C caregivers expected better psychological support and greater flexibility in weekly infusion schedules for their patients. CONCLUSIONS: The survey concluded that more attention must be paid to the psychosocial status of patients and caregivers. The preference for reference centre for follow-up and treatment, hospitalizations and surgeries were evident. The most significant needs expressed by the patients and caregivers include better understanding of the disease, pain management, monitoring of complications, flexibility in enzyme replacement therapy, home infusions especially for attenuated patients, and improved transitional support from paediatric to adult medicine.

Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. RESULTS: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001). CONCLUSION: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 .

Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa.

BACKGROUND: The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care. RESULTS: As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%]). CONCLUSIONS: MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data from the MPS I registry.

Mucopolysaccharidosis Type I (MPS I) is caused by deficiency of α-L-iduronidase. Short stature and growth deceleration are common in individuals with the attenuated MPS I phenotype. Study objectives were to assess growth in individuals with attenuated MPS I enrolled in The MPS I Registry while untreated and after initiation of enzyme replacement therapy (ERT) with laronidase (recombinant human iduronidase). Individuals in the MPS I Registry with at least one observation for height and assigned attenuated MPS I phenotype as of September 2020 were included. The cohort included 142 males and 153 females 2-18 years of age. Age and sex adjusted standardized height-for-age z-scores during the natural history and ERT-treatment periods were assessed using linear mixed model repeated measures analyses. Growth curves were estimated during both periods and compared to standard growth charts from the Center for Disease Control (CDC). There was a significantly slower decline in height z-scores with age during the ERT-treated period compared to the natural history period. Estimated average height z-scores in the ERT-treatment versus the natural history period at age 10 were -2.4 versus -3.3 in females and -1.4 versus -2.9 in males (females first treated 3 year; males <4.1 year). While median height remained below CDC standards during both the natural history and ERT-treated periods for individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores.

Acid Sphingomyelinase Deficiency: Sharing Experience of Disease Monitoring and Severity in France.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann-Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.

Determinants of Quality of Life in Children with Inborn Errors of Metabolism Receiving a Restricted Diet.

OBJECTIVE: To investigate the determinants of quality of life (QoL) in children with inborn errors of metabolism with restricted diet (IEMRDs) using a single theory-based multidimensional model. STUDY DESIGN: In this multicenter cross-sectional study, data from children aged 8-17 years with IEMRDs (except phenylketonuria) and their parents were collected from January 2015 to December 2017. Measurements included a child's self-reported QoL, self-rated behavioral problems and anxiety, and parental anxiety. Based on hypotheses from a literature-built theoretical model linking demographic, clinical, family environment, and psychosocial characteristics to QoL either directly or indirectly, associations of these factors with a child's self-rated QoL were examined using a structural equation modeling approach. RESULTS: A total of 312 children (mean [SD] age, 12.2 [2.6] years; 51% boys [n = 160]) were included. Higher levels of trait anxiety and behavioral problems in children were the most important factors associated with poorer QoL (standardized path coefficients, -0.71 and -0.23, respectively). In addition, higher parent trait anxiety, younger age at diagnosis, and a disease requiring an emergency diet were associated with poorer QoL in these children. The final model fit the data closely according to conventional goodness-of-fit statistics and explained 86% of the QoL variance. CONCLUSIONS: Psychosocial factors appear to be major determinants of QoL impairment in children with IEMRDs. These factors should be addressed in clinical practice as part of the global treatment plan for a child with IEMRD. Future studies based on a longitudinal design should consider coping strategies when exploring potential predictive factors of QoL.

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil.

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil-linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, noncomparative, single-dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency.

PURPOSE: To assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. METHODS: This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. RESULTS: Twenty patients were enrolled: four adolescents (12-17 years), nine children (6-11 years), and seven infants/early child (1-5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). CONCLUSION: In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months.

INTRODUCTION: Triheptanoin provides long-chain fatty acid oxidation disorder (LC-FAOD) patients with an alternative to medium-even-chain triglycerides therapy. MATERIAL-METHODS: Retrospective analysis of 18 French LC-FAOD patients benefiting from early access to triheptanoin treatment. RESULTS: Eight female and 10 male patients with LC-FAOD (VLCAD, LCHAD, CACT, CPTII and MTP) were treated with triheptanoin for a median duration of 22 months (range: 9-228 months). At last consultation, triheptanoin accounted for 15-35% of their daily caloric intake. In the year following the introduction of triheptanoin, patients reported a reduction of intermittent snacking and nocturnal meals. Three patients, including 1 adult, became free of severe hypoglycaemic events. Ten of 12 paediatric patients and 4 of 6 adult patients reported reduced fatigue with reductions in the number and severity of episodes of myalgia. Of 6 patients, including 1 adult, that had required the use of a wheelchair in the year prior to triheptanoin, all but one no longer required its use. The number of emergency hospitalizations decreased, and none were recorded for paediatric patients during these 12 months. Cumulative annual days of emergency care in the home were reduced from 286 to 51 days in the year before and after initiation, respectively, and 13 patients required no such interventions. Adverse events were limited to digestive issues that dissipated over time. CONCLUSIONS: Our case-series suggests that long-term treatment of LC-FAOD paediatric and adult patients with triheptanoin is safe and leads to marked improvement of symptoms and an improved quality of life.